Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:42])[C@@H:9]([C:33]([CH3:41])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:34])[CH2:10][NH:11][C@H:12]([C:17]([N:19]([CH3:32])[C@@H:20]([CH:29]([CH3:31])[CH3:30])/[CH:21]=[C:22](\[CH3:28])/[C:23]([O:25]CC)=[O:24])=[O:18])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.O.[OH-].[Li+]>CO>[C:1]([O:5][C:6]([N:8]([CH3:42])[C@@H:9]([C:33]([CH3:41])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:34])[CH2:10][NH:11][C@H:12]([C:17]([N:19]([CH3:32])[C@@H:20]([CH:29]([CH3:31])[CH3:30])/[CH:21]=[C:22](\[CH3:28])/[C:23]([OH:25])=[O:24])=[O:18])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC[C@@H](N(C)C(=O)OC(C)(C)C)C(C)(C)c1ccccc1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C/C(=C\[C@H](C(C)C)N(C)C(=O)[C@@H](NC[C@@H](N(C)C(=O)OC(C)(C)C)C(C)(C)c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Ethyl (2E,4S)-4-[(N-{(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutyl}-3-methyl-L-valyl)(methyl)amino]-2,5-dimethyl-2-hexenoate (50 mg, 0.085 mmol, Reference Example 20) is dissolved in methanol (1 ml), tetrahydrofuran (1 ml). To this solution is added water (0.5 ml) and solid lithium hydroxide (4.1 mg). The resulting mixture is stirred at room temperature for 15 hours. The organic solvents are removed in vacuo, and the residual aqueous mixture is cooled with an ice water bath, and acidified to pH 5.5-6.0 with aqueous 1N aqueous citric acid solution. The precipitate is collect by filtration, and the solid is washed with a cold water, and dried over high vacuum. Alternatively, the product can be purified by using preparative HPLC. (40 mg, 80%) MS [M+H] 588.2
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(CS(N)(=O)=O)cc1
Reaction time: 5 h
Yield: 97.3 %

Procedure:
To 10% palladium on charcoal catalyst (3 g, 50% wet with water) under a nitrogen atmosphere was added a solution of 4-nitro-benzylsulfonamide (17.53 g, 81.1 mmol). in dimethylformamide (175 ml). The atmosphere of nitrogen was replaced with hydrogen and the mixture stirred vigourously for 5 h. The atmosphere was replaced with nitrogen and the mixture filtered through celite. The solvent was removed in vacuo and the residue triturated with diethylether to give a dark brown solid (14.7 g). The solid was heated in acetonitrile (440 ml) and filtered whilst hot (to remove excess catalyst). The filtrate was allowed to cool and the precipitate filtered off and dried in vacuo to give the title compound as a beige solid (12.32 g, 82%). δH [2H6]—DMSO 4.05 (2H, s); 5.11 (2H, s); 6.53 (2H, d, 8.2 Hz); 6.63 (2H, s); 7.01(2H,d, 8.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O-:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]1([CH2:29][CH2:30][C:31]([OH:33])=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:34](N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:34])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:31](=[O:33])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1
Reactant: CC1(C)Cc2cc(C(=O)[O-])ccc2NC1c1cccc(N)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CCc1ccccc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)CCc3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
To an ice-cold mixture of 2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (150 mg, 0.48 mmol), 3-phenylpropanoic acid (95 mg, 0.73 mmol), N,N-diisopropyl ethylamine (0.20 mL, 1.16 mmol) in dichloromethane (10 mL) was added a solution of phosphorus oxychloride (0.06 mL, 0.63 mmol). Then the reaction mixture was stirred at room temperature overnight. LC-MS indicated that the starting material was consumed completely. Solvent was removed in vacuo and the residue was purified by Prep. Thin layer chromatography (petroleum ether/ethyl acetate=2:1) to afford 220 mg of methyl 3,3-dimethyl-2-(3-(3-phenylpropanamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; Yield: 90%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[S:12]([O-:15])([O-:14])=[O:13].[Na+].[Na+].O>C(O)C>[CH3:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[S:12]([OH:15])(=[O:14])=[O:13]
Reactant: Cc1ccc(C(=O)O)nc1Cl
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)O)nc1S(=O)(=O)O
Temperature: 180 °C
Yield: 111.2 %

Procedure:
6-chloro-5-methyl-pyridine-2-carboxylic acid (0.85 g, 4.97 mmol) and sodium sulfite (CAN 7757-83-7, 1.5 g, 11.9 mmol) were added to water (3 mL) and ethanol (3 mL). The mixture was heated to 180° C. for 4 h in a sealed tube. After that the mixture was cooled to room temperature and a solid precipitated that was removed by filtration. The filtrate was concentrated and added to water (20 mL). The aqueous phase was washed with ethyl acetate (2×20 mL). Subsequently the aqueous phase was adjusted to pH=2 with 2 N hydrochloric acid. Water was removed in vacuo to give the product as solid (1.2 g); MS (EI): m/e=218.0 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11]P(=O)(OCC)OCC.N#N.[Li]CCCC.[CH:27]([C:29]1[N:30]=[C:31]2[C:36]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:35][CH:34]=[N:33][N:32]2[C:43]=1[C:44]1[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=1)=O>C1COCC1>[O:40]1[CH2:39][CH2:38][N:37]([C:36]2[C:31]3[N:32]([C:43]([C:44]4[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=4)=[C:29](/[CH:27]=[CH:11]/[C:2]4[CH:3]=[CH:4][C:5]5[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=5[N:1]=4)[N:30]=3)[N:33]=[CH:34][CH:35]=2)[CH2:42][CH2:41]1
Reactant: CCOP(=O)(Cc1ccc2c(n1)CCCC2)OCC
Reactant: COC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C

Procedure:
A solution of compound 58b (0.70 g, 2.5 mmol) in THF (15 mL) was purged with N2. n-BuLi (2.5 M in hexane, 1.1 mL, 2.8 mmol) was added dropwise with stirring at rt and allowed to stir for 1 h. To the mixture was added compound 58c (0.70 g, 1.9 mmol). The resulting mixture was stirred overnight at rt, and quenched with saturated NH4Cl solution (100 mL). The resulting solution was extracted with DCM (3×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2 v/v)) to obtain compound 58d as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C29H29N5O3: 496.2 (M+H). Found: 496.2.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>>[C:12]1([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][C:3]3[S:4][C:5]4[C:10]([N:11]=3)=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)cc1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-phenylpiperazine (193 mg, 1.2 mmol), and DIEA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.74 (m, 4H) 3.19 (m, 4H) 4.05 (s, 2H) 6.78 (t, J=7.29 Hz, 1H) 6.95 (d, J=7.80 Hz, 2H) 7.22 (m, 2H) 7.56 (dd, J=8.15, 4.75 Hz, 1H) 8.33 (dd, J=8.15, 1.70 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 311 (M+H)+.
Reaction SMILES: FC(F)(F)C1C=C(C(F)(F)F)C(C(N)=O)=CC=1.[NH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[NH:24][C:25](=[O:40])[C:26]1[C:31]([S:32][CH3:33])=[CH:30][C:29]([C:34]([F:37])([F:36])[F:35])=[CH:28][C:27]=1[O:38][CH3:39].[I-].C([N+]1(C)[CH2:49][CH2:48][C:47](=[O:50])[CH2:46][CH2:45]1)C>>[CH3:39][O:38][C:27]1[CH:28]=[C:29]([C:34]([F:36])([F:37])[F:35])[CH:30]=[C:31]([S:32][CH3:33])[C:26]=1[C:25]([NH:24][CH:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[N:18]1[CH2:49][CH2:48][C:47](=[O:50])[CH2:46][CH2:45]1)=[O:40]
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Agent: NC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: [I-]
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCC(=O)CC1

Procedure:
The title compound, yellow gum, MS: m/e=431.3 [(M+H)+], was prepared in accordance with the general method of intermediate J from N-((1RS, 2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and 1-ethyl-1-methyl-4-oxo-piperidinium iodide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=O)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:27])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCCC2=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cccc2c1CCCC2N
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.8 %

Procedure:
To a stirred solution of (5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (10.0 g, 36.2 mmol) in methanol (300 mL) was added ammonium acetate (55.0 g, 714 mmol) at room temperature under nitrogen. After being stirred for 4 hours at room temperature, the reaction mixture was cooled to 0° C. and sodium cyanoborohydride (5.7 g, 90 mmol) was added. The resulting mixture was allowed to warm to room temperature and stirred for an additional 48 hours. The reaction mixture was then concentrated under reduced pressure. To the residue was added saturated sodium carbonate solution to adjust the pH to about 7, and the resulting solution was extracted with ethyl acetate (500 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (silica gel, 100-200 mesh, 2% to 5% methanol in dichloromethane) gave (5-amino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (4.6 g, 46%) as a solid. MS cald. for C16H23NO3 277. obsd. 278 [(M+H)+].
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].[OH-].[NH4+]>ClCCl>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:6]2[C:5](=[O:23])[CH2:4][CH:3]([NH:2][C:31](=[O:33])[CH3:32])[CH2:7]2)=[CH:13][CH:12]=1
Reactant: CC(=O)Cl
Reactant: NC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A solution of 25 mg (0.07 mmol) of (RS)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride in 1 ml of dichloromethane is treated with 22 μl (0.16 mmol) of triethylamine and cooled to 0° C. To this solution, 6 μl (0.08 mmol) of acetylchloride are added and stirring at 0° C. is continued for 30 min. For the working-up, the reaction mixture is treated with 2 ml of ammonium hydroxide solution, the organic phase separated, thereafter dried over sodium sulfate and evaporated under reduced pressure. For purification, the material obtained is chromatographed on silica gel using a 95:5 mixture of dichloromethane and methanol as the eluent. There are obtained 20 mg (78% of theory) of (RS)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=343 (M+H)+.
Reaction SMILES: O.[Cl-].[NH4+].[N+:4]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:8]=1)([O-])=O>C(O)C.[Fe]>[NH2:4][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:8]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N1CCOC1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(N)cc1N1CCOC1=O
Yield: 85.7 %

Procedure:
To a mixture of methyl 2-bromo-4-nitrobenzoate (2 g), oxazolidin-2-one (0.67 g), potassium carbonate (2.06 g), copper(I) iodide (0.73 g) and N,N′-dimethylethylenediamine (0.83 mL) was added toluene (16 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give methyl 4-nitro-2-(2-oxo-oxazolidin-3-yl)benzoate (960 mg). To a solution of ethanol (24 mL) and water (5 mL) were added ammonium chloride (0.11 g) and iron (0.79 g), and a solution of the obtained methyl 4-nitro-2-(2-oxooxazolidin-3-yl)benzoate (960 mg) in ethanol (19 mL) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give methyl 4-amino-2-(2-oxooxazolidin-3-yl)benzoate (730 mg). Using the obtained methyl 4-amino-2-(2-oxooxazolidin-3-yl)benzoate (730 mg) and 3-chloropropane-1-sulfonyl chloride (0.49 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (495 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[C:12]([S:15]([CH3:17])=[O:16])[S:13][CH3:14].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:25]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[C:12]([S:15]([CH3:17])=[O:16])[S:13][CH3:14])[C:3]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:2]=1[Cl:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSC(=Cc1ccccc1Nc1c(Cl)cccc1Cl)S(C)=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSC(=Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl)S(C)=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
In 25 ml of DMF, 3.8 g (0.010 mole) of 1-[o-(2,6-dichloroanilino)phenyl]-2-methylsulfinyl-2-methylthioethylene was dissolved and 0.98 g (0.022 mole) of sodium hydride (55%; oil dispersion) was added at 20° to 30° C. and the mixture was stirred at 80° C. for 1 hour and cooled to 20° C. and 44 g (0.026 mole) of benzyl bromide was further added and the mixture was stirred at room temperature (20° to 30° C.) for 12 hours and the reaction mixture was poured into a large amount of water to precipitate yellow crystals and the resulting crystals were filtered and dried under a reduced pressure and further recrystallized from benzene to obtain 4.5 g of 1-[N-benzyl-o-(2,6-dichloroanilino)phenyl]-2-methylsulfinyl-2-methylthioethylene as pale yellow crystals. Yield: 98%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:25][C:4]1[CH:3]=[C:2]([N:28]2[CH2:29][CH2:30][O:26][C:27]2=[O:31])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Reactant: O=C1NCCO1
Product: Cc1cc(N2CCOC2=O)ccc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Yield: 74.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (172 mg) described in Preparation Example 132 and oxazolidin-2-one (56 mg), the title compound (130 mg) was obtained.
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.C(O)[C:12]1[CH:17]=[CH:16]C=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:2]([O:7][C:6](=[O:8])[CH2:5][C:4]([OH:3])=[O:9])[C:10]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)CC(=O)OCc1ccccc1
Yield: 33.8 %

Procedure:
A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (25 g, 174 mmol) and benzyl alcohol (36 mL, 347 mmol) in toluene (100 mL) was heated at 106° C. for 24 h. The solution was poured into 5% Na2CO3 (aqueous), the organic layer was separated, and the aqueous layer was washed with ether (3×). The aqueous layer was then acidified with 1N HCl and extracted with ethyl acetate (2×). The combined ethyl acetate extracts were dried over anhydrous MgSO4, filtered and evaporated at reduced pressure to give malonic acid monobenzyl ester (11.42 g, 34%).
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6](C(O)=O)/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](=NC(OCC)=O)[O-])=O)C>O1CCCC1.CCOCC.CCCCC>[O:5]=[C:4]1[N:3]2[C@H:2]([O:11][C:7]([CH:8]=[CH2:9])=[CH:6]2)[CH2:1]1
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: CCOC(=O)N=[N+]([O-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC1=CN2C(=O)C[C@H]2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
Clavulanic acid (1.5 mmole) in dry tetrahydrofuran (5 ml) under a dry nitrogen atmosphere was treated with triphenylphosphine (1.5 mmole) and then, dropwise, diethylazoxicarboxylate (1.5 mmole) in dry tetrahydrofuran (2 ml). After addition was complete (2 minutes), the mixture was stirred for 30 minutes at room temperature and was then ice-cooled and diluted with a mixture of ether and n-pentane (1:2, 20 ml). The mixture was filtered and the filtrate was diluted with dry benzene (10 ml) and then concentrated to about 5 ml under reduced pressure to yield a solution of the title compound (1 mmole).
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O:14][P:15](COS(C(F)(F)F)(=O)=O)([O:17]CC)=[O:16])C.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[P:15]([C:10]1[CH:11]=[CH:2][CH:3]=[CH:4][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([OH:17])([OH:16])=[O:14]
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1P(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 139.8 %

Procedure:
A solution of methyl 4-hydroxybenzoate 111 (0.977 g, 6.42 mmol) and trifluoro-methanesulfonic acid diethoxy-phosphorylmethl ester (2.12 g, 7.06 mmol) in THF (50 mL) was treated with Cs2CO3 (4.18 g, 12.84 mmol). The resulting reaction mixture was stirred for 1 h at room temperature before it was partitioned between EtOAc and sat. aqueous NH4Cl and extracted with EtOAc (3×). The organic phase was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. Purification of the crude product on silica gel (eluted with 60-90% EtOAc/hexane) provided 1.94 g (quantitative) of methyl phosphonobenzoate compound 112 as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH2:14]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: CNc1nc(Cl)nc2ccccc12

Procedure:
Prepared as in Example 38 from 2,4-dichloroquinazoline and methylamine. 1H NMR (400 MHz, DMSO-d6) δ2.98 (d, J=4.4 Hz, 3H), 7.53-7.49 (m, 1H), 7.61-7.58 (m, 1H), 7.79-7.75 (m, 1H), 88.19-8.17 (m, 1H), 78 (bs, 1H).
Reaction SMILES: [S:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.I([O-])(=O)(=O)=O.[Na+].[OH2:33].[CH3:34]O>>[S:1](=[C:2]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:34]1)=[O:33]
Reactant: O
Reactant: CO
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CS4)c(F)c2)C(=O)O1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CC4=S=O)c(F)c2)C(=O)O1
Yield: 57 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-thia-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.4 mmol) and sodium periodate (mmol) in methanol water mixture (10 ml) at a temperature 25-30° C. for 14 hours in 57% yield.
Reaction SMILES: N1C=CN=C1.[Br:6][CH2:7][CH2:8]CCCCCCO.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].CN(C)[CH:26]=[O:27]>O1CCCC1>[Br:6][CH2:7][CH2:8][CH2:26][O:27][Si:20]([CH3:22])([CH3:21])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)C=O
Reactant: OCCCCCCCCBr
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCBr
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.55 g of imidazole were added to a solution of 3.97 g of 8-bromo octanol in 19 ml of dimethylformamide, and over 10 minutes, 3.32 g of tertbutyl chloro dimethyl silane in solution in 4,7 ml tetrahydrofuran were added. The mixture was stirred for one hour at ambient temperature and the insoluble part was filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed on silica (eluant: cyclohexane-toluene 8-2) to obtain 5.4 g of the expected product.
Reaction SMILES: C(O[C:4](=O)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)C.CCOCC>C1COCC1>[CH3:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)NC1CCCc2ccccc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN[C@H]1CCCc2ccccc21
Temperature: 75 °C
Reaction time: 2 h

Procedure:
(1,2,3,4-Tetrahydro-naphthalen-1-yl)carbamic acid ethyl ester (5.0 g, 22.8 mmol) is added slowly under nitrogen to a suspension of LiAlH (2.6 g, 68 mmol) in THF (50 mL). The resulting mixture is heated at 75° C. with stirring for 2 h. On cooling, Na2SO4.10H2O (15.0 g) and ether (100 mL) are added to the mixture. The resulting mixture is stirred at room temperature for 1 hour, filtered through celite, and concentrated in vacuo. 1 N HCl (20 mL) and ether (20 ML) are added to the residue. The organic layer is separated and discarded. The aqueous layer is basified with 1 N NaOH and extracted with CH2Cl2 (2×25 mL). The combined extract is washed with water (2×), dried (Na2SO4) and concentrated to give (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine as an oil. [α]RT=−10.6 (0.02, EtOH). 1H NMR (CDCl3) 7.30 (m, 1H), 7.06-7.20 (m, 3H), 3.66 (t, 1H), 2.78 (m, 2H), 2.50 (s, 3H), 1.70-2.00 (m, 4H).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].Cl[CH2:6][CH2:7][CH2:8][C:9](=O)[CH2:10][CH2:11][CH2:12]Cl.[NH3:15].CO>>[N+:1]([CH2:4][C:9]12[CH2:10][CH2:11][CH2:12][N:15]1[CH2:6][CH2:7][CH2:8]2)([O-:3])=[O:2]
Reactant: O=C(CCCCl)CCCCl
Reactant: N
Reactant: C[N+](=O)[O-]
Solvent: CO
Product: O=[N+]([O-])CC12CCCN1CCC2
Temperature: 20 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To a solution of nitromethane (0.67 g, 11 mmol) in 0.3 ml of 16% NH3 /MeOH, 1,7-dichloro-4-heptanone (0.50 g, 2.7 mmol) was added dropwise at 20° C. The resulting solution was stirred for 24 hours at 20° C. under ammonia gas atmosphere. The reaction mixture was concentrated and 0.1N NaOH was added to the residue to extract with methylene chloride. The extract was dried over anhydrous sodium sulfate, concentrated and distilled in vacuo to afford 0.42 g of the desired compound (Yield: 90%).